Failure to achieve selective toxicity (or therapeutic index) and development of multidrug resistance are major problems in cancer chemotherapy. Glutathione S-transferase Pl-l isoform (GSTpi) is elevated in most cancer cells-- especially chemoresistant ones. This makes GSTpi a potential means for enhancing therapeutic index and targeting resistant tumors. We have designed several prototypes to release toxins in the presence of GSTpi. Feasibility will be demonstrated both in vitro and in vivo using tumor cells containing high GSTpi levels. Increased toxicity in elevated GSTpi versus low GSTpi controls is the expected outcome. A team of experts in GSTpi oncology/enzymology and synthetic chemistry are assembled to test this new approach. The agents could eventually lead to a much needed chemotherapeutic for treating cancer which has become resistant to commonly used cancer treatment regimens. Approximately 1/2 of the chemotherapy patients do not make it into remission due to unresponsive tumors as well as high toxicity (low therapeutic index). PROPOSED COMMERCIAL APPLICATION: The proposed research could lead to a new chemotherapeutic agent to treat both chemosensitive and chemoresistant tumors. If it is successful, such an agent is expected to have a substantial market.